The focus of this project is the use of MRI to understand the pathophysiology of multiple sclerosis (MS) and to determine whether disease activity is altered by various immunomodulatory treatments and to investigate the natural history of lesions. In a relatively small cohort of patients the temporal relationship between inflammation and cerebral atrophy in a longitudinal study using serial monthly contrast enhanced MRI examinations and monthly measurements of brain fractional volume (BFV) for an average of 4 (range 2.4 to 10) years. Cerebral atrophy paralleled that of contrast enhancing lesion accumulation in these patients. The correlation between cumulative enhancing lesions and atrophy ranged from R2 = 0.47 to 0.81. Immunomodulatory agents such as interferon that effectively reduced CEL accumulation also slowed the rate of atrophy. The correlation between contrast enhancing lesions and atrophy suggests that patients who are not responding to therapy with a decrease in inflammation on MRI may also be at risk for developing increased atrophy. Chronic, hypointense black holes (BHs) are recognized as a sign of permanent damage in patients with multiple sclerosis. Although the effects of interferon beta-1b in reducing the formation of new BHs are established, it is not clear whether the drug may reduce BH duration after these lesions are formed. MS patients were scanned for 3 years prior to and after starting treatment with interferon beta-1b revealed that the Rate of BH accumulation decreased with treatment (P = .01), but Kaplan-Meier models revealed that the duration of BHs did not shorten. Interferon beta-1b reduces the frequency of new BH formation but does not appear to decrease their duration in time.